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At least 1,153 records · Page 64Linked to original sources
PubMed2005

Clinical effectiveness and cost-effectiveness of drotrecogin alfa (activated) (Xigris) for the treatment of severe sepsis in adults: a systematic review and economic evaluation.

OBJECTIVES: To assess the clinical and cost-effectiveness of drotrecogin alfa (activated) for the treatment of adults with severe sepsis in a UK context. DATA SOURCES: Electronic databases. Data from the commercial use of the drug up to April 2002. Data from the manufacturer submission to the National Institute for Clinical Excellence (NICE). REVIEW METHODS: A systematic review of the literature and an economic evaluation were undertaken. Data were synthesised through a narrative review with full tabulation of results from included studies. RESULTS: The evidence on the effectiveness of drotrecogin alfa (activated) for the treatment of severe sepsis came primarily from one large pivotal randomised controlled trial, the PROWESS study. This study demonstrated a statistically significant absolute reduction in 28-day mortality of 6.5%. Longer term survival benefit was maintained to 90 days. By 9 months, the trend towards increased median survival was non-significant, although the survival curves did not cross. Results presented by the number of organ dysfunctions were not statistically significant, but when mortality rates for those with two or more organ failures were combined, the relative risk of death was significantly lower in those treated with drotrecogin alfa (activated) compared with placebo. However, this report highlights a number of considerations relevant to the subgroup analyses reported for the PROWESS study. Published cost-effectiveness studies of treatment with drotrecogin alfa (activated) have applied a range of methods to the estimation of benefits, estimating an incremental gain per treated patient of between 0.38 and 0.68 life-years (for patients with severe sepsis). For patients with severe sepsis and multiple organ dysfunction, the manufacturer (Eli Lilly) estimated an incremental gain of 1.115 life-years per treated patient, compared to 1.351 life-years per treated patient estimated by the Southampton Health Technology Assessments Centre (SHTAC). These latter UK analyses are based on a patient group that is more severely affected by disease, where effectiveness is greater and the baseline risk of all-cause mortality is much higher (SHTAC analysis), these factors are associated with the noted difference in effect. The three published cost-effectiveness studies report cost for US and Canadian patient groups; for those patients with severe sepsis they report the additional cost per patient treated in a range around 10,000-16,000 dollars. The manufacturer's submission reports analysis for the UK, based on 28-day survival data in patients with severe sepsis and multiple organ dysfunction (the European licence indication), with the additional mean cost per treated patient estimated to be 5106 pounds. The analysis undertaken by SHTAC, for a UK group of patients with severe sepsis and multiple organ dysfunction, estimates an additional mean cost per patient treated of 6661 pounds. The manufacturer's submission to NICE presents cost-effectiveness estimates for drotrecogin alfa (activated) in the UK, in patients with severe sepsis and multiple organ dysfunction, at 6637 pounds per quality-adjusted life-year (QALY) based on 28-day effectiveness data, and 10,937 pounds per QALY based on longer term follow-up data. SHTAC developed an independent cost-effectiveness model and estimated a base-case cost per QALY of 8228 pounds in patients with severe sepsis and multiple organ failure (based on 28-day survival data). Simulation results indicate that where the NHS is willing to pay 20,000 pounds per QALY, drotrecogin alfa (activated) is a cost-effective use of resources in 98.7% of cases. Published economic evaluations report various sensitivity analyses, with results sensitive to changes in the measure of treatment effect, but otherwise studies reported that results were robust to variations in most assumptions used in the cost-effectiveness analysis. CONCLUSIONS: Drotrecogin alfa (activated) plus best supportive care appears clinically and cost-effective compared with best supportive care alone, in a UK cohort of severe sepsis patients, and in the subgroup of more severely affected patients with severe sepsis and multiple organ failure. The introduction of drotrecogin alfa (activated) will involve a substantial additional cost to the NHS. The treatment-eligible population in England and Wales may comprise up to 16,570 patients, with an estimated annual drug acquisition cost of over 80 million pounds, excluding VAT. Further research is required on the longer term impact of drotrecogin alfa (activated) on both mortality and morbidity in UK patients with severe sepsis, on the clinical and cost-effectiveness of drotrecogin alfa (activated) in children (under 18 years) with severe sepsis, and on the effect of the timing of dosage and duration of treatment on outcomes in severe sepsis.

Adolescent↗
PubMed2006

The health care crisis of childhood-onset bipolar illness: some recommendations for its amelioration.

OBJECTIVE: To describe new data on the incidence and impact of childhood- and adolescent-onset bipolar illness and make recommendations to help accelerate the acquisition of knowledge in this area. DATA SOURCES: Two large, multicenter out-patient studies in adults with DSM-IV bipolar disorder-the Systematic Treatment Enhancement Program for Bipolar Disorder and the Bipolar Collaborative Network-were the primary sources of retrospective data on age at onset. STUDY SELECTION: We focused on the 2 retrospective studies because they supplied more immediate data on age at onset and long-term prognosis than current prospective studies. DATA SYNTHESIS: The 2 studies revealed that 15% to 28% of adults experienced an onset of their illness prior to age 13 years. Those with childhood versus adult onset had a more severe, complicated, and adverse course of bipolar illness, assessed retrospectively and confirmed prospectively during naturalistic treatment. The time lag from onset of first symptoms to first treatment was strongly inversely related to age at onset and averaged 16.8 +/- 10 years in those with childhood onset. Recommendations include defining temporary consensus threshold criteria for each bipolar subtype and their prodromes; conducting studies using less onerous than traditional designs, including randomized open comparisons to acquire preliminary data in this age cohort; and forming clinical and academic treatment outcome networks to more quickly acquire treatment outcome data in this understudied population. CONCLUSIONS: The data reveal a very substantial rate of childhood-onset bipolar illness, extraordinary delays in onset to first treatment, and a very adverse long-term outcome. Several approaches to accelerating the rate of acquisition of treatment outcome data in this cohort are outlined.

Adolescent↗
PubMed1993

Triplets and quadruplets born in Victoria between 1982 and 1990. The impact of IVF and GIFT on rising birthrates.

OBJECTIVES: To examine the perinatal characteristics of all higher order multiple births (133 sets of triplets and six sets of quadruplets) in the State of Victoria between 1982 and 1990. To compare the rising higher order multiple birth rates in Victoria with those in the other States of Australia, and to assess the impact of in-vitro fertilisation (IVF) and gamete intrafallopian transfer (GIFT) on these rising birth rates. DESIGN: Retrospective review of all higher order multiple births registered in Victoria and other States of Australia between 1982 and 1990, and in particular those resulting from IVF and GIFT. DATA SOURCES: Victorian Perinatal Data Collection Unit, Australian Bureau of Statistics, National Perinatal Statistics Unit, data from Victorian IVF and GIFT units. MAIN OUTCOME MEASURES: Higher order multiple birth rates and perinatal mortality rates. RESULTS: The higher order multiple birth rates in Victoria rose from 3.5 per 10,000 in 1982 to 10.9 per 10,000 in 1990. The average perinatal mortality rates for the Victorian triplets and quadruplets born during this period were 10.8% and 25.0%, respectively. The rates of caesarean section were 70% and 83%; the proportions of deliveries in level III hospitals, 75% and 100%; and the mean maternal lengths of stay in hospital, 32 and 57 days, respectively. Endotracheal intubation was performed at birth in 18.5% of all infants. The proportions of triplet and quadruplet pregnancies in Victoria owing to IVF and GIFT rose during this period, reaching a peak of 42% in 1990. In the other States, the birth rates for higher order multiples increased at 1.8 times the rate observed for Victoria, with IVF and GIFT contributing to an estimated 43% of these conceptions between 1985 and 1989. CONCLUSION: Restrictions on the numbers of embryos/oocytes transferred during IVF and GIFT should reduce the frequency of higher order multiple births.

Adult↗
PubMed2001

Australian medical patents granted in the United States in 1984-1999.

OBJECTIVE: To describe all medical patents granted in the United States to Australian-resident inventors between 1984 and 1999. DATA SOURCES: All patent data originated from the US Patent and Trademark Office. Data for 1984-1994 were compiled by CHI Research Inc, and data for 1995-1999 were obtained from the Community of Science website. MAIN OUTCOME MEASURES: Number of medical patents granted in the US to Australian-resident inventors; assignees (owners) of these medical patents; proportion of these medical patents related to biotechnology. RESULTS: From 1984 to 1999, 7835 utility patents were granted in the US to Australian-resident inventors. Of these, 1308 patents (17%) were identified as medical patents; 489 (37%) of these were biotechnology patents. Medical patents account for an increasing proportion of all US patents granted to Australian inventors, increasing from 10% in 1984 to 25% in 1999. Biotechnology accounted for an increasing proportion of medical patents, rising from 10% to 55% between 1984 and 1999. More than half the medical patents are owned by commercial interests, and 33% by only 14 organisations, six of which are universities and their affiliated institutions. CONCLUSION: Only a few organisations account for most of the patenting of medical technology. The inventors and their organisations listed on medical patents could be canvassed when developing government policy and targeted for support in commercialising their medical technology.

Australia↗
PubMed2000

Watchful waiting with periodic liver biopsy versus immediate empirical therapy for histologically mild chronic hepatitis C. A cost-effectiveness analysis.

BACKGROUND: Not all patients with histologically mild chronic hepatitis C progress to cirrhosis. OBJECTIVE: To compare no antiviral treatment, periodic liver biopsy with subsequent antiviral treatment for moderate hepatitis or cirrhosis, and immediate antiviral therapy. DESIGN: Cost-effectiveness analysis. DATA SOURCES: Clinical trial data and published studies. TARGET POPULATION: Hepatitis C virus-infected patients with histologically mild hepatitis. TIME HORIZON: Lifetime. PERSPECTIVE: Societal. INTERVENTION: Immediate combination antiviral treatment or biopsy every 3 years plus combination antiviral therapy for moderate hepatitis or cirrhosis. OUTCOME MEASURES: Life expectancy, quality-adjusted life expectancy, and costs. RESULTS OF BASE-CASE ANALYSIS: Over 20 years, biopsy every 3 years with treatment of moderate hepatitis would avoid treatment in 50% of the cohort and would result in an 18% likelihood of cirrhosis compared with 16% for immediate treatment and 27% for no antiviral therapy. Immediate antiviral treatment should increase life expectancy by 1.0 quality-adjusted life-year compared with biopsy management. Over an average lifetime, biopsy management would lead to six liver biopsies costing $6200; immediate antiviral treatment would cost $5100 less than biopsy management because of savings related to biopsy and prevention of future hepatitis C-related morbidity. Immediate therapy was cost-effective compared with biopsy management and had a cost-effectiveness ratio of $7000 compared with no antiviral therapy. RESULTS OF SENSITIVITY ANALYSIS: When age, sex, genotype, and estimates of histologic progression or compliance with follow-up are varied, immediate therapy should result in an increase of at least 0. 8 quality-adjusted life-year compared with biopsy management. CONCLUSION: For histologically mild chronic hepatitis C, initial combination treatment compared with periodic liver biopsy should reduce the future risk for cirrhosis, prolong life, and be cost-effective.

Adult↗
PubMed2002

Economic analysis of influenza vaccination and antiviral treatment for healthy working adults.

BACKGROUND: Physicians have several treatment options for influenza, including vaccination and various antiviral therapies. However, the optimal influenza prevention and treatment strategy is unknown. OBJECTIVE: To compare the relative health values of contemporary treatment strategies for influenza in a healthy sample of working adults. DESIGN: Cost-benefit analysis using a decision model. DATA SOURCES: Previously published data. TARGET POPULATION: Healthy employed adults 18 to 50 years of age. TIME HORIZON: A complete influenza season. PERSPECTIVE: Societal. INTERVENTIONS: Eight treatment options (yes or no) based on the possible combinations of vaccination and antiviral therapy (rimantadine, oseltamivir, or zanamivir or no treatment) should infection develop. OUTCOME MEASURES: Cost in U.S. dollars, including the value of symptom relief and medication side effects, which was assigned a monetary value through a conjoint analysis that used a "willingness-to-pay" approach. RESULTS: In the base-case analysis, all strategies for influenza vaccination had a higher net benefit than the nonvaccination strategies. Vaccination and use of rimantadine, the most cost-beneficial strategy, was $30.97 more cost-beneficial than nonvaccination and no use of antiviral medication. The health benefits of most antiviral treatments equaled or exceeded their costs for most scenarios. The choice of the most cost-beneficial antiviral strategy was sensitive to the prevalence of influenza B and to the comparative workdays gained by each antiviral therapy. CONCLUSIONS: Vaccination is cost-beneficial in most influenza seasons in healthy working adults. Although the benefits of antiviral therapy for persons with influenza infection appear to justify its cost, head-to-head trials of the various antiviral therapies are needed to determine the optimal treatment strategy.

Acetamides↗
PubMedDate not supplied

Amniotic fluid tests for fetal lung maturation--the good, the bad, and the promising.

OBJECTIVE: To assess promising laboratory tests for fetal lung maturity (FLM). DATA SOURCES: Professional literature. DATA EXTRACTION: Survey of literature. DATA SYNTHESIS: Traditional biochemical tests for FLM such as the LSR are reliable if performed properly but are difficult to perform, costly, and not widely available; most are not good predictors of respiratory distress syndrome. Many of the newer biochemical and biophysical FLM assays are more reliable, faster, require less personnel time, and are readily available. CONCLUSION: The development of laboratory tests to measure the presence or effects of pulmonary surfactant in amniotic fluid has contributed greatly to the management of premature deliveries; newer tests show promise but require more extensive evaluation.

Agglutination Tests↗
PubMedDate not supplied

A method for developing outcome measures in the clinical laboratory.

Measuring and reporting outcomes in health care is becoming more important for quality assessment, utilization assessment, accreditation standards, and negotiating contracts in managed care. How does one develop an outcome measure for the laboratory to assess the value of the services? A method is described which outlines seven steps in developing outcome measures for a laboratory service or process. These steps include the following: 1. Identify the process or service to be monitored for performance and outcome assessment. 2. If necessary, form an multidisciplinary team of laboratory staff, other department staff, physicians, and pathologists. 3. State the purpose of the test or service including a review of published data for the clinical pathological correlation. 4. Prepare a process cause and effect diagram including steps critical to the outcome. 5. Identify key process variables that contribute to positive or negative outcomes. 6. Identify outcome measures that are not process measures. 7. Develop an operational definition, identify data sources, and collect data. Examples, including a process cause and effect diagram, process variables, and outcome measures, are given using the Therapeutic Drug Monitoring service (TDM). A summary of conclusions and precautions for outcome measurement is then provided.

Data Collection↗
PubMed1999

Variations in primary care physician referral rates.

OBJECTIVE: To examine primary care physician referral rate variations, including their extent and their stability over time and across diagnostic categories. DATA SOURCES: 1995/1996 claims data for adult patients from a large Independent Practitioner Association (IPA) model managed care organization (MCO) in the Rochester, NY metropolitan area. The IPA includes over 95 percent of area primary care physicians (PCPs), and the MCO includes over 50 percent area residents. STUDY DESIGN: Referral rates (patients referred to and seen by specialists one or more times/patients seen by PCP/year) were developed for the PCPs (457 general practitioners, family physicians, and internists) in the MCO, including observed referral rates, expected referral rates based on case-mix adjustment across the whole sample, physician-specific case mix-adjusted referral rates (empirical Bayes estimates), and diagnostic category-specific case mix-adjusted referral rates. PRINCIPAL FINDINGS: Wide variations in observed referral rates (0.01-0.69 patients referred/patients seen/year) were attenuated relatively little by case-mix adjustment and persisted in case mix-adjusted empirical Bayes estimates (0.02-0.65). The year-to-year case mix-adjusted referral rate correlation was .90. Correlations of case mix adjusted-referral rates across diagnostic categories were moderate (r=.46-.67). CONCLUSIONS: PCP referral rates exhibit wide variations that are independent of case mix, remain stable over time, and are generalizable across diagnostic categories. Understanding this physician practice variation and its relationship to costs and outcomes is critical to evaluating the effect of current efforts to reduce PCP referral rates.

Adult↗
PubMed1983

Managing programs for the elderly: design of a social information systems.

This paper describes a comprehensive approach to assembling a health care information system to monitor programs for the elderly and disabled in a cost effective manner. The Social Information System (SIS) described in the paper was implemented for the evaluation of the New York State Long-Term Home Health Care Program (LTHHCP). This evaluation required the collection and organization of large amounts of client specific data, including claims, clinical and programatic data. Sources for these data included client medical records, Medicare, Medicaid, and the New York State Food Stamps, Public Assistance, Title XX, and Energy Assistance Programs. Recommendations are made regarding client identification, data elements, access, and structure of the data base.

Home Care Services↗
PubMed1999

A claims data approach to defining an episode of care.

OBJECTIVE: To utilize health services research techniques in developing an episode of care using an administrative data set. This method is demonstrated for an episodic clinical condition, migraine. DATA SOURCES: Medicaid administrative data set of 3,372 patients with a diagnosis of migraine (ICD-9-CM 346.0, 346.1) in the state of Pennsylvania between May 1990 and March 1992. STUDY DESIGN: The duration of a migraine episode was measured by assessing the magnitude of resource utilization and the proportion of patients with charges in the period after the index migraine as compared to the period before the index migraine. A confidence interval (CI) was developed around each measure using bootstrap techniques. DATA COLLECTION METHODS: All charge data were extracted daily for a 113-day observation period surrounding each index migraine in order to observe the duration of impact of a migraine diagnosis on resource utilization. PRINCIPAL FINDINGS: The lower limits of both the 95% and 99% CIs for the difference in charges are greater than 0 for three weeks. The lower limits of both CIs for the difference in the proportion of patients with charges are above 0 for six weeks. CONCLUSIONS: Our analysis demonstrates that a health services research framework can be used to define an episode of care for a chronic disease category such as migraine. This method can be used to evaluate episodes of care for clinical studies of limited or episodic conditions and to complement clinical expertise in developing time horizons for clinical trials.

Adult↗
PubMed1998

Alveolar echinococcosis in China.

DATA SOURCES: All reference data originated from related Chinese- or English-language literature in Chinese journals. STUDY SELECTION: Twenty-three original articles published in 1992-1996 were selected according to the stated purpose and 9 of them were written by myself. DATA EXTRACTION: The present paper dealt with 5 subtopics, i.e. epidemiology, parasitology, pathology, diagnosis, treatment and prognosis. RESULTS: Five hundred and eighty-four patients with alveolar echinococcosis (AE) have been reported from 7 provinces or autonomous regions. Human infection rate was 19.2% or 2.8%, and the morbidity was 2.4%-5.0%. The intermediate hosts of Echinococcus multilocularis included 7 species of rodents and 3 species of livestocks, and the final hosts of that were fox, dog or wolf. Diagnosis of AE was chiefly based on imaging examination (ultrasound and CT) and immunological test. The operative resection rate for liver AE was only 10.5% (27/258). Albendazole was a certain remedy for the chemotherapy of AE, and TCM "Xiao-Bao" pill may be a hopeful drug. CONCLUSIONS: In the past 30 years, a lot of work concerning basic and clinical studies has been done in China and some achievements have been achieved. However, some important problems such as how to conduct further research on molecular biology, how to make early diagnosis, how to improve the chemotherapeutic effect, and how to control the prevalence of AE, need to be studied more deeply in the 21st century.

Animals↗
PubMed1999

Benchmarking organ procurement organizations: a national study.

OBJECTIVE: An exploratory examination of the technical efficiency of organ procurement organizations (OPOs) relative to optimal patterns of production in the population of OPOs in the United States. DATA SOURCES: A composite data set with the OPO as the unit of analysis, constructed from a 1995 national survey of OPOs (n = 64), plus secondary data from the Association of Organ Procurement Organizations and the United Network for Organ Sharing. STUDY DESIGN: The study uses data envelopment analysis (DEA) to evaluate the technical efficiency of all OPOs. PRINCIPAL FINDINGS: Overall, six of the 22 larger OPOs (27 percent) are classified as inefficient, while 23 of the 42 smaller OPOs (55 percent) are classified as inefficient. Efficient OPOs recover significantly more kidneys and extrarenal organs; have higher operating expenses; and have more referrals, donors, extrarenal transplants, and kidney transplants. The quantities of hospital development personnel and other personnel, and formalization of hospital development activities in both small and large OPOs, do not significantly differ. CONCLUSIONS: Indications that larger OPOs are able to operate more efficiently relative to their peers suggest that smaller OPOs are more likely to benefit from technical assistance. More detailed information on the activities of OPO staff would help pinpoint activities that can increase OPO efficiency and referrals, and potentially improve outcomes for large numbers of patients awaiting transplants.

Benchmarking↗
PubMed1999

Changes in children's hospital use.

OBJECTIVES: This article examines changes in hospital separations of children aged 1 to 14 between 1986/87 and 1996/97. It focuses on four common causes of childhood hospitalization: asthma, chronic disease of tonsils and adenoids, fractures, and acute appendicitis. DATA SOURCES: Hospital separation data are from the Hospital Morbidity File, from Statistics Canada for fiscal year 1986/87, and from the Canadian Institute for Health Information for fiscal year 1996/97. ANALYTICAL TECHNIQUES: Diagnoses were coded to the International Classification of Diseases, Ninth Revision and surgical procedures were coded to the Canadian Classification of Diagnostic, Therapeutic, and Surgical Procedures. Population estimates for 1986 and 1996 were used to calculate hospital separation rates and surgical rates. MAIN RESULTS: In 1986/87, there were 355,000 hospital separations of children aged 1 to 14; by 1996/97, the number of separations had fallen to just over 206,000. The hospital separation rate was 37.0 per 1,000 children in 1996/97, down from 69.7 ten years earlier. The average length of stay fell from 4.5 days to 3.8. The total annual number of days Canadian children stayed in hospital dropped from over 1.6 million to 788,700.

Adolescent↗
PubMed1999

[Epidemiology of diabetes type 1 in the 0 to 29 year-old age group in Northeastern Poland, 1994-1998--prospective observations].

It was recently suggested that there is a tendency of the rising incidence of diabetes type 1 in different countries in Europe. In our previous studies we observed the high frequency of ICA among first degree relatives of diabetic subjects, what could suggest a rapid increase in the incidence of diabetes type 1 also in the north-eastern region of Polan. The aim of the study was to estimate the annual incidence of diabetes type 1 in the north-eastern region of Poland and to evaluate the association of the incidence rates with the age, gender, urban-rural differences and the season of the year of the disease onset. The register of new cases of IDDM was established in 1994 using 2 independent data sources. The degree of ascertainment was 98.9% for the combination of both data sources. We observed a rising trend in the incidence from 6.4 in 1994 to 9.9 cases per year per 100,000 in 1998 (p < 0.001). The highest incidence rate increase was recorded in boys aged 5 to 14 years old (16-17 cases per 100,000 in 1997-1998). The rising trend in this incidence was observed in the rural areas, while in urban populations the incidence was unchanged. Seasonal variation in the incidence was also recorded, with a peak in autumn and winter and nadir in summer. Our observations suggest the necessity of the continuation of the studies to identify the diabetogenic environmental factors and to try preventive procedures in the studied population.

Adolescent↗
PubMed2000

The effect of Employee Assistance Programs use on healthcare utilization.

OBJECTIVE: To estimate the effect of Employee Assistance Program (EAP) use on healthcare utilization as measured by health claims. DATA SOURCES: A unique data set that combines individual-level information on EAP utilization, demographic information, and health insurance claims from 1991 to 1995 for all employees of a large midwestern employer. STUDY DESIGN: Using "fixed-effect" econometric models that control for unobserved differences between individuals' propensities to use healthcare resources and the EAP, we perform our analyses in two steps. First, for those employees who visited the EAP, we test whether post-EAP claims differ from pre-EAP claims. Second, we combine claims data of individuals who went to an EAP with those of individuals who did not use an EAP to test whether differences in utilization exist between EAP users and nonusers. DATA COLLECTION METHODS: From the EAP we obtained the date of first EAP contact for all employees who used the service, and from the company's human resources department we obtained limited demographic data on all employees. We obtained healthcare utilization claims data on all employees and their dependents from the company's two healthcare plans: a fee-for-service (FFS) plan and a health maintenance organization (HMO) plan. PRINCIPAL FINDINGS: We found that going to an EAP substantially increases both the probability of an alcohol, drug abuse, or mental health (ADM) claim and the number of ADM claims in the same quarter as EAP contact. The increased probability of an ADM claim persists for approximately 11 quarters after the initial contact, while the increased ADM charges persist for approximately six quarters after the initial EAP contact. CONCLUSIONS: Our results strongly suggest that the EAP is able to identify behavioral and other health problems that may affect workplace performance and prompt EAP users to access ADM and other healthcare. Consistent with the stated goals of many EAPs, including the one examined in this study, this process should improve individuals' health, family functioning, and workplace performance.

Alcoholism↗
PubMed2000

Acute promyelocytic leukemia (AML-M3)--Part 2: Molecular defect, DNA diagnosis, and proposed models of leukemogenesis and differentiation therapy.

OBJECTIVES: To identify the chromosomal translocation common in M3 and discuss its diagnostic use to: Compare acute leukemia with chronic leukemia and other forms of cancer. Describe the molecular defect including the fusion gene and fusion protein produced from the translocation. Discuss the proposed mechanism of leukemogenesis in M3. Discuss the proposed mechanism of differentiation induction stimulated by ATRA therapy. Present the future direction of this and other forms of therapy. DATA SOURCES: Current literature. DATA SYNTHESIS: Acute promyelocytic leukemia (AML-M3) is a form of acute leukemia that presents with a less dramatic leukocytosis, anemia, and thrombocytopenia than other acute leukemias. However, AML-M3 has a lower first remission rate and a higher morbidity and mortality rate than most of the other acute leukemias when treated with conventional chemotherapy. AML-M3 frequently stimulates a serious concomitant coagulation disorder, disseminated intravascular coagulation, which is a major contributor to the high mortality rate. This and other devastating sequela of M3 have prompted clinicians and investigators to develop methods of improving diagnosis and therapy. In 1977 the method of diagnosis confirmation was improved by the identification of a consistent chromosomal translocation involving the long arms of chromosomes 15 and 17. Identification of the specific molecular lesion that produced the t(15;17) translocation occurred in 1990 and was shown to involve the retinoic acid receptor alpha gene (RAR alpha). Because the RAR alpha gene is mutated in all AML-M3 patients studied so far and because it is often the only mutation identified, several proposed mechanisms of leukemogenesis have evolved. From these discoveries a novel approach to cancer treatment focusing on differentiation therapy instead of traditional chemotherapy emerged. All-trans retinoic acid (ATRA) has been shown to stimulate differentiation of promyelocytes from the malignant clone and has become an important element in the treatment of patients with AML-M3. CONCLUSION: Since the discovery of the t(15;17) translocation, the identification of the fusion gene containing the retinoic acid receptor alpha, and the success of ATRA as a form of differentiation therapy, the diagnosis and treatment of AML-M3 has dramatically improved. In addition, AML-M3 has become a model system used to study the mechanisms that produce uncontrolled growth and lack of differentiation in leukemic cells (leukemogenesis) and the mechanisms of therapeutic reversal of this block in differentiation (differentiation therapy).

Antineoplastic Agents↗
PubMed2000

Acute promyelocytic leukemia (AML-M3)--Part 1: Pathophysiology, clinical diagnosis, and differentiation therapy.

OBJECTIVES: The objectives of this review paper are to: Compare acute leukemia with chronic leukemia and other forms of cancer. Review the pathophysiology and discuss the clinical and diagnostic features of M3. Describe the variant of M3 (M3m or M3v). Compare conventional chemotherapy with all-trans retinoic acid differentiation therapy (ATRA) in the treatment of M3. Discuss the future direction of differentiation therapy. DATA SOURCES: Current literature. DATA SYNTHESIS: Until the late 1970s, the methods of diagnosis and treatment of AML-M3 were similar to the other forms of acute myelocytic leukemia. One notable difference between M3 and other acute myelocytic leukemias involved the common occurrence of life-threatening consumptive coagulopathies in M3 patients that dramatically affected patient outcomes. In 1977 the method of diagnosis confirmation was altered by the identification of a consistent chromosomal translocation involving the long arms of chromosomes 15 and 17. Reports in the 1970s and 1980s indicated that certain types of active metabolites of vitamin A, collectively termed retinoids, could induce differentiation in a variety of cancer derived cell lines, in vitro. It was shown in the early 1980s that 13-cis-retinoic acid (13cRA) could stimulate differentiation in bone marrow cells collected from patients with various acute leukemias, including M3. The first clinical trial of a retinoid, given as a remission induction therapeutic regimen, involved all-trans retinoic acid (ATRA) administered to M3 patients in 1988. Since then, ATRA therapy has been shown to reduce tumor burden by stimulating differentiation of the leukemic cells, induce long-term clinical remission when administered in conjunction with chemotherapy, and lower the incidence of consumptive coagulopathies in patients with AML-M3. CONCLUSION: The diagnosis and treatment of AML-M3 has improved dramatically in the past decade, which has greatly enhanced the prognosis of patients with this disease. First remission rates have increased to greater than 85% world wide, the incidence of disseminated intravascular coagulation (DIC) has declined dramatically, and 60% to 70% of patients with AML-M3 have achieved long term survival and are potentially cured.

Antineoplastic Agents↗